Ovarian Carcinosarcoma with Retroperitoneal Para-Aortic Lymph

diagnostics

Case Report Ovarian Carcinosarcoma with Retroperitoneal Para-Aortic Lymph Node Dissemination Followed by an Unusual Postoperative Complication: A Case Report with a Brief Literature Review

Stoyan Kostov 1 , Yavor Kornovski 2, Yonka Ivanova 2, Deyan Dzhenkov 3 , George Stoyanov 3, Stanislav Stoilov 1, Stanislav Slavchev 2 , Ekaterina Trendaﬁlova 2 and Angel Yordanov 4,*

1 Department of Gynecology, Medical University of Varna “Prof. Dr. Paraskev Stoyanov”, 9002 Varna, Bulgaria; [email protected] (S.K.); [email protected] (S.S.) 2 Department of Obstetrics and Gynecology, Medical University of Varna “Prof. Dr. Paraskev Stoyanov”, 9002 Varna, Bulgaria; [email protected] (Y.K.); [email protected] (Y.I.); [email protected] (S.S.); doctortrendaﬁ[email protected] (E.T.) 3 Department of General and Clinical Pathology, Forensic Medicine and Deontology, Faculty of Medicine, Medical University of Varna “Prof. Dr. Paraskev Stoyanov”, 9002 Varna, Bulgaria; [email protected] (D.D.); [email protected] (G.S.) 4 Department of Gynecologic Oncology, Medical University Pleven, 5800 Pleven, Bulgaria * Correspondence: [email protected]; Tel.: +359-98-8767-1520

Received: 18 October 2020; Accepted: 9 December 2020; Published: 11 December 2020

Abstract: Introduction. Ovarian carcinosarcoma (OCS), also known as malignant mixed Müllerian tumour (MMMT), is one of the rarest histological subtypes of ovarian cancer. It is an aggressive tumour with a dismal prognosis—the median survival of patients is less than two years. The rarity of the disease generates many controversies about histogenesis, prognostic factors and treatment of OCS. Histologically, OCS is composed of an epithelial and sarcomatous component. Case report. In the present case, a patient with bilateral ovarian cysts and bulky paraaortic lymph nodes is reported. Retroperitoneal paraaortic lymph node metastases were the only extrapelvic dissemination of OCS. The patient underwent comprehensive surgical staging procedures, including total abdominal hysterectomy and bilateral salpingo-oophorectomy, supracolic omentectomy and selective para-aortic lymphadenectomy. Histologically the ovarian carcinosarcoma was composed of an epithelial component (high-grade serous adenocarcinoma) and three sarcomatous components (homologous—endometrial stromal cell sarcoma, and heterologous—chondrosarcoma, rhabdomyosarcoma). Immunohistochemistry staining was performed. A postoperative complication (adhesion between the abdominal aorta and terminal ileum causing obstructive ileus) that has never been reported in the medical literature occurred. Conclusion. Carcinosarcomas are carcinomas with epithelial–mesenchymal transition and heterologous differentiation. Retroperitoneal pelvic and paraaortic lymph nodes should be carefully inspected in patients with ovarian tumours. Adhesions between the small bowels and abdominal aorta are possible complications after lymph node dissection in the paraaortic region.

Keywords: ovarian carcinosarcoma; paraaortic lymph node metastasis; diagnosis; treatment

1. Introduction Ovarian cancer is the ﬁfth most common cause of cancer death among women, and ninety percent of ovarian cancers are of an epithelial cell type, while sex cord-stromal tumours and malignant ovarian germ cell tumours are relatively rare [1]. Ovarian carcinosarcoma (OCS), also known as

Diagnostics 2020, 10, 1073; doi:10.3390/diagnostics10121073 www.mdpi.com/journal/diagnostics Diagnostics 2020, 10, 1073 2 of 15 malignant mixed Müllerian tumour (MMMT), is one of the rarest histological subtypes of ovarian cancer. OCS represents 1–4% of all ovarian tumours [2,3]. OCS can be found in the genito-urinary tract with the most common site being the uterus, followed by the ovary, fallopian tubes, cervix, vagina, peritoneum, breast and urethra [3,4]. Histologically, OCS is composed of an epithelial and sarcomatous component—homologous (i.e., having Müllerian pathology) and heterologous [2,4]. At the time of diagnosis, about half of the patients have ascites, and one in two patients will already have pelvic and para-aortic lymph node metastases [3]. OCS is an aggressive tumour with a dismal prognosis—the median survival of patients less than two years [2,5]. Prognostic factors remain controversial due to the rarity of the tumour. There is also little consensus about the most eﬀective treatment, although optimal cytoreductive surgery and platinum-based chemotherapy appear to improve the outcomes [6,7]. In the current case study, a case of a female patient with bilateral ovarian OCS treated with optimal cytoreductive surgery is reported. An unusual postoperative complication occurred. An ethical committee approval (number 546 /30.10.2019) was obtained for it.

2. Case Report A 53-year-old postmenopausal woman (gravida 1, para 1) presented at the Department of Gynecology with a short history of abdominal pain and abdominal distension. She had no relevant history of urogenital malignancy and no vaginal bleeding. She did not have a medical history of gynaecological problems, hormone therapy, or any major medical diseases—diabetes mellitus, cardiovascular, or renal issues. Gynaecological examination revealed two large palpable, relatively mobile, non-tender masses in the pelvic region. Abdominal and vaginal ultrasonography showed two ovarian tumours of maximum diameter—left tumour 12 cm, right tumour—10 cm, composed of solid and non-solid masses with mixed echogenicity—hypoechoic and hyperechoic components. There was free fluid in the pouch of Douglas. According to the International Ovarian Tumour Analysis (IOTA), bilateral ovarian tumours were classified as malignant: irregular solid tumours, presence of ascites, and very strong blood flow [8,9]. The chest X-ray showed no pleural effusion or pulmonary metastases. Computed tomography and measurement of tumour marker levels were not performed. Laboratory data results were normal. Suspicion for ovarian malignancy prompted an exploratory midline laparotomy from above the umbilicus to the symphysis pubis [7]. During surgery, the abdominal and retroperitoneal lymph nodes were inspected precisely. Haemorrhagic ascites of 300 mL was presented in the peritoneal cavity. There were no macroscopic metastases in the liver, gall-bladder, greater and lesser omentum, alimentary organs and pelvic lymph nodes. Bulky paraaortic lymph nodes, suspected for lymph node metastases were palpated. Ascites fluid analysis was obtained. Frozen section from the left adnexal tumour revealed malignancy. The patient underwent comprehensive surgical staging, including total abdominal hysterectomy and bilateral salpingo-oophorectomy, supracolic omentectomy, and selective para-aortic lymphadenectomy. During para-aortic lymphadenectomy, the inferior mesenteric artery was ligated due to metastatic lymph node dissemination. Lesions of the inferior vena cava were also observed. Thumbtack was applied followed by ligation with an absorbable suture 4-0. Total blood loss was 500 mL (Figure1). Diagnostics 2020, 10, 1073 3 of 15 Diagnostics 2020, 10, x FOR PEER REVIEW 3 of 15

Figure 1. ParaaorticParaaortic lymphadenectomy. lymphadenectomy. (A (A) Resection) Resection of ofbulky bulky paraaortic paraaortic lymph lymph nodes nodes suspected suspected for lymphfor lymph node node metastases; metastases; (B) Paraaortic (B) Paraaortic region region after lymphade after lymphadenectomy;nectomy; AA—abdominal AA—abdominal aorta; IVC— aorta; inferiorIVC—inferior vena cava; vena LRV—left cava; LRV—left renal vein; renal LOV—left vein; LOV—left ovarian vein, ovarian cut and vein, ligated cut and where ligated it drains where into it thedrains left intorenal the vein; left renalIMAL—inferior vein; IMAL—inferior mesenteric mesentericartery, cut and artery, ligated; cut and IVCL—inferior ligated; IVCL—inferior vena cava severedvena cava during severed pelvic during lymphadenectomy, pelvic lymphadenectomy, IVC was sutured IVC waswith sutured 4/0 absorbable with 4/ 0suture; absorbable LA—lumbar suture; artery;LA—lumbar PMM—psoas artery; PMM—psoas major muscle; major LCIA—left muscle; common LCIA—left iliac common artery; iliacLCIV—left artery; LCIV—leftcommon iliac common vein; PR—promontory;iliac vein; PR—promontory; RCIA—right RCIA—right common commoniliac artery iliac; UR—ureter; artery; UR—ureter; EIA—external EIA—external iliac artery; iliac artery;IIA— internalIIA—internal iliac artery; iliac artery; ROV—right ROV—right ovarian ovarian vein; vein; ROVL ROVL—right—right ovarian ovarian vein vein ligated ligated where where it drains it drains in inferiorin inferior vena vena cava; cava; (C) ( CParaaortic) Paraaortic lymph lymph nodes nodes removed removed en enmasse. masse.

The gross appearance of the ovarian tumours was soft and fleshy, fleshy, with haemorrhage and necrosis. Both Both fallopian fallopian tubes tubes were were infiltrated, infiltrated, while while the the uterus uterus was was without macroscopic pathological changes. changes. A A histopathological histopathological examination examination revealed revealed OCS OCS in both in both ovaries, ovaries, infiltrating infiltrating both fallopianboth fallopian tubes. tubes. Histologically, Histologically, the OCS the was OCS compos was composeded of epithelial of epithelial component component (high-grade (high-grade serous adenocarcinoma)serous adenocarcinoma) and three and threesarcomatous sarcomatous compon componentsents (homologous—endometrial (homologous—endometrial stromal stromal cell sarcoma, and heterologous—chondrosarcoma,heterologous—chondrosarcoma, rhabdomyosarcoma). Immunohistochemistry (IHC) staining forfor cytokeratincytokeratin shows shows di ffdiffuseuse intense intense staining staining of the of epithelial the epithelial element, element, while desmin while stainingdesmin stainingexhibits rhabdomyosarcomatousexhibits rhabdomyosarcomatous components. components. Histologically, Histologically, rhabdomyosarcomatous rhabdomyosarcomatous components werecomponents predominant were atpredominant more than 25%. at more The expressionthan 25%. The of p53 expression protein was of negativep53 protein for bothwas sarcomatousnegative for bothand carcinomassarcomatous components. and carcinomas The components. number of para-aorticThe number lymph of para-aortic nodes removed lymph nodes en masse removed during en masselymphadenectomy during lymphadenectomy was 19—all with was metastatic 19—all cancer with spread metastatic from thecancer epithelial spread component from the (high-grade epithelial componentserous carcinoma). (high-grade Greater serous and carcinoma). lesser omentum Greate andr and uterus lesser were omentum without and metastases. uterus were Cytological without metastases.findings from Cytological the ascites findings revealed from adenocarcinoma the ascites revealed cells. The adenocarcinoma patient was diagnosed cells. The with patient surgical was diagnosedstage IIIA1 with according surgical to stage the latest IIIA1 International according to Federationthe latest International of Gynecology Federation and Obstetrics of Gynecology (FIGO) and Obstetrics (FIGO) classification, and pT2aN1bMx, according to the TNM classification [10]. On post-surgery day 10, the patient was discharged from the hospital in good health condition (Figures 2–4).

Diagnostics 2020, 10, 1073 4 of 15 classiﬁcation, and pT2aN1bMx, according to the TNM classiﬁcation [10]. On post-surgery day 10, the patient was discharged from the hospital in good health condition (Figures2–4). Diagnostics 2020,, 10,, xx FORFOR PEERPEER REVIEWREVIEW 4 of 15

Figure 2. (A(A) )Microphotographs Microphotographs of of the the tumour tumour show showinginging carcinomacarcinoma carcinoma andand and sasa sarcomarcoma components— components— H&Ex200-carcinomatous with high-grade serous carcinoma carcinoma and and sarcomatoussarcomsarcomatous component with stromal and chondroidchondroid differentiation.differentiation. Red Red arro arrows—serousws—serous epithelial epithelial carcinoma; carcinoma; black black arrows— arrows— chondrosarcoma; yellowyellow arrows—endometrialarrows—endometrial stromalstromal sarcoma.sarcoma. ( B) Metastatic lymph lymph node—HEx100 node—HEx100 lymphlymph node node withwith metastasesmetastases ofof carcinomatouscarcinomatous (high-grade (high-grade serous) serous) component. component. BlackBlack arrows—lympharrows—lymph node metastases fromfrom thethe epithelialepithelial component.component.

Figure 3. Starburst appearance in the sarcomatous component typical for stromal sarcoma, H&Ex200. Figure 3. StarburstStarburst appearance in the sarcomatous comp componentonent typical for stromal sarcoma, H&Ex200.

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Figure 4.4. ImmunohistochemicalImmunohistochemical staining staining (IHC). (IHC). ( (AA)) IHC IHC with with cytokeratin 7—diffuse 7—diffuse and strong cytoplasmic positivitypositivity in in malignant malignant epithelial epithelial cells cells of high-of high- grade grade serous serous component component of the of tumour, the tumour,200 × magnification;×200 magnification; (B) IHC (B with) IHC desmin with whichdesmin shows which cytoplasmic shows cytoplasmic positivity ofpositivity sarcomatous of sarcomatous component withcomponent smooth with muscle smooth diff erentiation,muscle differe100ntiation, magnification; ×100 magnification; (C) IHC with (C) p53IHC whichwith p53 shows which that shows both × componentsthat both components are negative, are magnificationnegative, magnification200. ×200. × On post-surgery day 15, the patient was admitted again at the Department of Gynecology with abdominal distension, abdominal pain, fever 38.2 °C,◦C, vomiting, and reduced intestinal peristalsis. Abdominal andand vaginal vaginal sonography sonography showed showed free fluid free in fluid the abdominal in the abdominal cavity. Computed cavity. tomographyComputed demonstratedtomography demonstrated postoperative ileuspostoperative and a high ileus amount and of a freehigh fluid amount in the of abdominal free fluid cavity. in the The abdominal patient’s laboratorycavity. The resultspatient’s revealed laboratory hyperproteinaemia results revealed andhyperproteinaemia hypoalbuminemia. and hypo The chestalbuminemia. X ray was The without chest abnormalities.X ray was without After abnormalities. surgeon consultation, After surgeon conservative consultation, treatment conservative was initiated. treatment Relaparotomy was initiated. was performedRelaparotomy as thewas patient’s performed symptoms as the persistedpatient’s forsymptoms 72 h. Abdominal persisted wallfor 72 dehiscence h. Abdominal at the levelwall ofdehiscence the umbilicus at the level was observed.of the umbi Duringlicus was the observed. operation, During up to the 4 operation, L of lymph up fluid to 4 L were of lymph evacuated fluid fromwere theevacuated abdominal from cavity. the abdominal A cytology cavity. and A microbiology cytology and examination microbiology was examination obtained. was Sigmoid obtained. and transverseSigmoid and colon transverse were dilatated. colon Adhesionwere dilatated. between Adhesion the terminal between ileum the and terminal the abdominal ileum aortaand justthe belowabdominal the superior aorta just mesenteric below the artery superior was mesenteric noticed. Adhesiolysis artery waswas noticed. achieved. Adhesiolysis Nasogastric wasintubation achieved. wasNasogastric obtained. intubation was obtained. Two drainsdrains werewere leftleft inin thethe abdominalabdominal cavity.cavity. The abdominal wall was closed and reinforced with synthetic mesh. Metal skin staples were also used during abdominal surgical wound closure. closure. Postoperative empiricalempirical antibiotics—ceftriaxone antibiotics—ceftriaxone (2 (2 g g every every 12 12 h, h, i.v., i.v., 5 days), 5 days), and and metronidazole metronidazole (500 (500 mg everymg every 8 h, i.v.,8 h, 5 days),i.v., 5 and days), albumin and infusionalbumin therapyinfusion was therapy initiated. was On initiated. the next threeOn the postoperative next three days,postoperative the patient days, was the subfebrile patient was with subfebrile normal with peristalsis normal and peristal diuresis.sis and The diuresis. nasogastric The nasogastric tube was removed.tube was removed. Total blood Total loss blood was 300 loss mL. was Microbiology 300 mL. Microbiology and cytology and examinations cytology examinations detected no detected bacterial florano bacterial and no flora tumour and cells.no tumour On post-surgery cells. On post-surgery day 7, drains day were7, drains removed. were removed. On post-surgery On post-surgery day 10, theday patient10, the waspatient discharged was discharged without complaintswithout complaints (Figures5 (Figuresand6). On 5 and post-surgery 6). On post-surgery day 21, metal day skin 21, staplesmetal skin were staples removed. were The removed. patient The made patient an uneventful made an uneventful postoperative postoperative recovery. recovery.

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Figure 5. (A) Abdomen just before relaparotomy; (B) computed tomography showed postoperative FigureFigure 5. (A 5.) Abdomen(A) Abdomen just just before before relaparotomy; relaparotomy; ((B) computed tomography tomography showed showed postoperative postoperative ileus and elevated amount of free fluid. ileusileus and elevatedand elevated amount amount of of free free ﬂuid. fluid.

Figure 6. (A) Adhesion between terminal ileum and abdominal aorta causing obstructive ileus; MR— mesentery, TI—terminal ileum, AA—abdominal aorta; (B) dilatated caecum. Diagnostics 2020, 10, 1073 7 of 15

3. Discussion OCS is a rare tumour, which represents one of the most highly aggressive cancers of the female genital tract with poor long-term prognosis [7]. OCS is usually encountered after menopause, with a median age of 65 years [11]. Risk factors are the same as for ovarian carcinomas and sarcomas: obesity, nulliparity, exogenous oestrogen, radiotherapy and long-term Tamoxifen use [7]. Patients usually have advanced disease at the time of diagnosis. The majority of patients are Caucasian and present with stage III–IV disease and spread beyond the ovary (>90%) at the time of diagnosis [4,11–13]. MMMT has a worse survival rate than high-grade ovarian cancer at the same FIGO stage, as approximately 75% of reported patients die of the disease in an average of 12 months postoperatively. MMMT is also disseminated earlier than ovarian cancer [2,13]. MMMT staging is the same as for ovarian cancer [11]. In the present case, the patient was under 65 years, with no risk factors and with advanced-stage disease—FIGO IIIA1. It is hard to distinguish MMMT and ovarian cancer preoperatively, as both malignancies have the same clinical and radiological findings [11]. The clinical presentation of MMMT is the same as the ovarian carcinoma. The most common symptoms are abdominal pain, distension, early satiety, bloating, nausea, vomiting, and weight loss [5,11,14]. The spread pattern of OCS is the same as that of ovarian carcinoma—peritoneal dissemination at the early sites of spreading [6]. Although both sarcoma and carcinoma components are seen in metastatic diseases, OCS rarely metastasizes in the lung and brain, unlike its uterine counterpart [14]. Serum CA-125 levels are elevated in the majority of cases [11]. Three theories have been suggested to explain the histogenesis of gynaecological carcinosarcoma: biclonal (collision) and monoclonal (combination and conversion) theories. The collision theory suggests that carcinoma and sarcoma are two independent tumours originating from a separate cell, which later merge. The combination theory assumes that sarcoma and carcinoma components are derived from a single stem cell and undergo divergent differentiation early in tumour evolution. The conversion theory states that an epithelial cell undergoes metaplasmic differentiation that initiates tumour genesis and gives rise to a sarcomatous component, and these tumours should be regarded as dedifferentiated carcinomas of the ovary [1,12,14]. Latest studies extrapolate that carcinosarcomas are carcinomas with epithelial–mesenchymal transition and heterologous differentiation [1,12–15]. Studies communicate that monoclonal (combination and conversion) theories are not mutually exclusive [1,12,14,15]. As OCS is a rare disease, most of the studies on the genetic origin of carcinosarcoma (CS) in gynaecologic tumours come from uterine carcinosarcoma specimens [14]. Some studies utilize the protein p53expression to explain the monoclonal theory, as OCS has been reported to overexpress p53 in a higher proportion [1,14]. The consistent concordance of p53 staining between the carcinomatous and sarcomatous elements in OCS (p53 protein expression is either negative or positive for both components) supports the monoclonal theory: if these were transverse colons, such concordance in all cases would be extremely unlikely [14,15]. Mayall et al. concluded that disparities in the presence of p53 gene mutation between the epithelial and stromal components prove the biclonal theory, whereas if carcinosarcomas were monoclonal, then disparities would not occur [16]. Although the mutation of the p53 gene does not always cause p53 immunostaining, most of the immunostained for p53 tumours have a p53 gene mutation [16]. The present case also supports the theory of common origin for the epithelial and mesenchymal elements, as the pattern of p53 immunostaining in the epithelial and stromal components of carcinosarcomas was investigated. The p53 expression was negative for both components. Other studies, which support carcinosarcoma theory, include clonality studies, genomic analysis, loss of heterozygosity, gene mutations, and expressions [1,14]. Cases describing ovarian carcinoma recurring as OCS support the conversion theory [17,18]. The three theories are demonstrated in Figure7. Diagnostics 2020, 10, 1073 8 of 15

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FigureFigure 7. Collision Collision theory: theory: CarcinomaCarcinoma (blue (blue cells) cells) and andsarcoma sarcoma (brown (brown cells) are cells) two are independent two independent neoplasms,neoplasms, which which later later merge; merge; CombinationCombination theory: theory: both componentsboth components are derived are from derived a single from stem a single cell that undergoes divergent differentiation early in the evolution of the tumour; Conversion theory: stem cell that undergoes divergent differentiation early in the evolution of the tumour; Conversion the sarcomatous element is derived from the carcinoma during tumour evolution (pink cells— theory: the sarcomatous element is derived from the carcinoma during tumour evolution (pink cells— epithelial–mesenchymal transition). epithelial–mesenchymal transition). Histologically, OCS is composed of an epithelial (endometrioid, clear cell, serous, mucinous, Histologically, OCS is composed of an epithelial (endometrioid, clear cell, serous, mucinous, squamous, undifferentiated), as well as of a sarcomatous component (homologous—fibrosarcoma, squamous,leiomyosarcoma, undi fferentiated),endometrial as wellstromal as of a sarcomatoussarcoma, componentor heterologous—osteosarcoma, (homologous—fibrosarcoma, leiomyosarcoma,rhabdomyosarcoma, endometrial liposarcoma stromal or chondrosarcoma sarcoma, or heterologous—osteosarcoma,). Immunohistochemistry (IHC) rhabdomyosarcoma, staining for liposarcomacytokeratin and or chondrosarcoma). epithelial membrane Immunohistochemistry antigen showed diffuse (IHC) intense staining staini forng cytokeratin of the epithelial and epithelial membraneelement, while antigen the showedmesenchymal diffuse component intense staining usually ofstains the epithelial for vimentin, element, smooth while muscle the mesenchymal actin, componentdesmin, and usuallyfocal cytokeratin stains for [1,19]. vimentin, Positive smooth CK7 and muscle negative actin, CK20 desmin, staining and support focal cytokeratin Mullerian [1,19]. Positiveorigin [1]. CK7 In andthe present negative case, CK20 cytokeratin staining and support desmin Mullerian were used origin for [epithelial1]. In the and present mesenchymal case, cytokeratin andcomponents. desmin wereTypical used for stromal for epithelial sarcoma, and a star mesenchymalburst appearance components. was noticed Typical macroscopically. for stromal sarcoma, a starburstThe rarity appearance of the disease was generates noticed macroscopically. many controversies about the prognostic factors of OCS. Some studiesThe conclude rarity of that the older disease age, generatesadvanced stage many at controversiespresentation, and about suboptimal the prognostic surgical resection factors of OCS. Someare associated studies conclude with poor that outcome older age, [6,14]. advanced High Ca-125 stage atlevels presentation, at presentation and suboptimal are an unfavourable surgical resection prognostic factor [20]. Most of the prognostic factors are accessed based on histopathological are associated with poor outcome [6,14]. High Ca-125 levels at presentation are an unfavourable examination of the specimen: epithelial carcinoma grade, myometrial vascular invasion, type of prognostic factor [20]. Most of the prognostic factors are accessed based on histopathological epithelial and sarcomatous components, presence of sarcomatous components, vascular endothelial examinationgrowth factor of(VEGF), the specimen: vascular en epithelialdothelial growth carcinoma factor grade, receptor myometrial 3 (VEGFR-3) vascular expression, invasion, number type of epithelialof small vessels and sarcomatous and stromal sarcoma components, predominance presence in ofthe sarcomatous primary tumour. components, Tumour protein vascular p53 endothelialand growthantigen factorKi67 obtained (VEGF), by vascular immunohi endothelialstochemical growth staining factor are receptor also prognostic 3 (VEGFR-3) factors expression, [1,6,14,20–26]. number of smallStudies vessels establish and the stromal following sarcoma most significant predominance prognostic in the factors primary correlated tumour. with Tumour better prognosis: protein p53 and antigenpatient’s Ki67 age, obtainedtumour stage by immunohistochemical at diagnosis, type of surgery, staining epithelial are also carc prognosticinoma histologic factors [grade,1,6,14 ,20–26]. Studiesepithelial establish component the histology following and most type significant of adjuvant prognostic chemotherapy factors [1,6,14, correlated20–26]. In with conclusion, better prognosis:the patient’sprognosis age, of carcinosarcomas tumour stage at is diagnosis, derived from type the of surgery,epithelial epithelial component. carcinoma Prognostic histologic factors related grade, to epithelial componentthe sarcomatous histology components and type have of adjuvant no longer chemotherapy any prognostic [ 1significance,6,14,20–26 ].[1,6,14,20–26]. In conclusion, Most the of prognosis the of carcinosarcomasprognostic factors is in derived OSC mentioned from the epithelialin the medical component. literature Prognostic are summarized factors in related Table 1 to [1,6,14,20– the sarcomatous 26]. components have no longer any prognostic significance [1,6,14,20–26]. Most of the prognostic factors in OSC mentioned in the medical literature are summarized in Table1[1,6,14,20–26]. In the present case, the patient had 7 favourable (<65 years, optimal surgical resection, no myometrial vascular invasion, no sarcomatous components outside the ovary, no stromal predominance in the primary tumour, absent p53 overexpression, adjuvant platinum-based therapy), and 6 unfavourable prognostic factors (advanced initial tumour stage, high-grade serous carcinoma, Diagnostics 2020, 10, 1073 9 of 15 serous epithelial components, presence of sarcomatous components in the primary tumour > 25%, heterologous sarcoma components, a high number of small vessels). Tests for Ca-125 levels, Ki67 reactivity, VEGF, and VEGFR-3 expression were not performed.

Table 1. Prognostic signiﬁcance of various prognostic factors relevant to ovarian carcinosarcoma.

Prognostic Factors Favourable Unfavourable Patient’s age <65 years >65 years Initial tumour stage Early Advanced Surgery Optimal surgical resection Suboptimal surgical resection Ca-125 levels at presentation Low High Epithelial carcinoma histologic grade Low High Myometrial vascular invasion No Yes Epithelial components Non-serous Serous Sarcomatous components Homologous Heterologous Sarcomatous components outside the ovary No Yes Presence of sarcomatous components <25% >25% Histological stromal sarcoma predominance No Yes Number of small vessels in the primary tumour Low High VEGF, VEGFR-3 expression Normal Increased P53 overexpression Absent Presented Ki67 reactivity Low High Adjuvant chemotherapy Platinum-based regimens Non-platinum-based regimes Legend: VEGF—Vascular endothelial growth factor; VEGFR-3—Vascular endothelial growth factor receptor 3; P53—protein 53; Ki67—antigen Ki67.

The treatment suggestion of MMMT is based mainly on small retrospective studies or extrapolations from research on epithelial ovarian cancer or uterine carcinosarcoma [27]. The initial therapy of OCS is optimal surgical cytoreduction including total abdominal hysterectomy, bilateral adnexectomy, omentectomy, selective pelvic and para-aortic lymph node dissection to the left renal vein, and tumour debulking [2]. Systematic lymphadenectomy for the advanced stage is not recommended [28]. However, the definition of optimal cytoreduction has changed over the years. Currently, optimal cytoreduction is defined as no macroscopic residual disease [29]. Although the role of cytoreduction in ovarian carcinoma is well established, some studies have reported no benefit of cytoreduction in OCS [4,30,31]. Duska et al. reported that optimal cytoreduction increased the disease-free interval, but not the overall survival. In the majority of studies, optimal surgery is correlated with better progression-free and overall survival in carcinosarcoma, and complete cytoreduction should be the goal of surgical treatment [11,32,33]. Fertility-sparing surgery in patients with OCS is not recommended regardless of age or stage. However, if the patient chooses fertility-sparing surgery, a hysterectomy is recommended after childbearing [34]. Establishing the most effective adjuvant chemotherapeutic regimen in OCS remains elusive [2,35]. Platinum-based chemotherapy is the most commonly used adjuvant treatment as it has been found to be superior to no platinum-based regimes [1,6,14,28]. In a study, the authors reported that doxorubicin was inadequate as single-agent chemotherapy: it was shown to be insufficient, and a poor response rate and high toxicity were observed [4,36]. Different platinum-based regimes have been used over the years. In a study of 31 patients with OCS, the outcomes between patients treated with carboplatin/paclitaxel compared to those treated with ifosfamide/paclitaxel have been compared. The authors concluded that median progression free-survival (PFS) was longer in patients treated with carboplatin/paclitaxel, whereas overall survival (OS) was similar for all treatment groups [37]. Another study of 31 patients with OCS compared ifosfamide/cisplatin vs. carboplatin/taxol. PFS and OS showed improvement with the use of ifosfamide/cisplatin [33]. Heinzelmann-Schwarz et al. reported that in endometrial carcinosarcoma platinum/anthracycline or ifosfamide regimens were associated with better outcomes than platinum/taxanes regimens so that these findings might be applied to OCS [38]. Yalcin et al. compared the prognosis of patients with OCS to patients with ovarian high-grade serous Diagnostics 2020, 10, 1073 10 of 15 carcinoma treated in the same manner: optimal cytoreductive surgery followed by platinum plus taxane combination chemotherapy. They stated that the therapeutic approaches could be identical for patients with either diagnosis as PFS and OS were similar for patients with OCS and ovarian high-grade serous carcinoma [39]. However, Brown et al. reported for 65 patients with MMMT and 746 patients with serous ovarian adenocarcinoma selected as a comparison group. They concluded that OCS had an inadequate response to platinum-based chemotherapy, and worse progression-free and cause-specific survival compared to serous ovarian adenocarcinoma [40]. Loizzi et al. treated 13 patients with OCS and compared adjuvant chemotherapy based on the combination of cisplatin, epirubicin and ifosfamide (PEI) or taxol and carboplatin (TAX-CBDCA). They concluded that the median OS was not statistically different between the PEI and TAX-CBDCA regimen groups. However, higher toxicity has been observed in the PEI group [41]. Currently, the National Comprehensive Cancer Network (NCCN) guidelines recommend that paclitaxel 175 mg/m2/carboplatin (three to nine cycles) is the preferred adjuvant chemotherapy regimen for OCS stage I. Other recommended regimens are carboplatin/liposomal doxorubicin or docetaxel/carboplatin. In certain circumstances carboplatin/ifosfamide, cisplatin/ifosfamide, and paclitaxel/ifosfamide might be used [34]. In stage II–IV, paclitaxel/carboplatin/bevacizumab + maintenance bevacizumab, are added as first-line treatment. Paclitaxel weekly/carboplatin weekly and paclitaxel weekly/carboplatin q 3 weeks are additional second-line treatment regimens. NCCN stated that data on primary systemic therapy regimes for OCS are limited [34]. Neoadjuvant chemotherapy should be considered if optimal debulking cannot be achieved, or for patients who are poor candidates for surgery due to a high risk of operative morbidity or extra-abdominal disease [28]. Intravenous taxane/carboplatin and liposomal doxorubicin/carboplatin regimens are recommended [34]. Nizam et al. reported on two patients who underwent neoadjuvant chemotherapy with 3 cycles of carboplatin/taxol and optimal cytoreductive surgery in one patient, and suboptimal cytoreductive surgery in the other one, respectively [42]. Hyperthermic intraperitoneal chemotherapy (HIPEC) is under consideration, as it is an acceptable treatment option for ovarian cancer, but there are no published data specifically for carcinosarcoma. The combination of intravenous and intraperitoneal chemotherapy is possible [1,3]. The necessity for adjuvant radiotherapy (external beam irradiation and/or vaginal brachytherapy) has not shown any overall survival benefit but has been reported to decrease local recurrence [3,7]. Although there is no evidence against the beneficial effect of radiotherapy, it may be used for patients with chemotherapy-refractory, recurrent or persistent disease that is restricted to the pelvis [12,43]. Nizam et al. reported on two patients with OCS treated with adjuvant radiation therapy. One patient had axillary metastases and the other one axillary recurrence after optimal debulking surgery. They are currently alive [42]. Geisler et al. examined nine cases of OCS and found receptors for oestrogen in six of the cases and no receptor for progesterone [44]. In another study of uterine carcinosarcomas, receptors for oestrogen and progesterone were found in four of 11 cases [45]. These findings could suggest the possibility of hormone therapy as a potential therapeutic alternative. Given the rarity of the disease, there are limited data regarding the relevance of targeted therapies. Overexpression of COX-2, HER-2/neu, C-kit in carcinosarcomas has been reported [1]. Consequently, agents like imatinib (targeting C-kit) and tyrosine kinase inhibitor (TKI) neratinib (targeting HER-2/neu) may provide an opportunity for targeted therapies [1]. A recent case study reported a significant tumour response in a patient with OCS to the poly (ADP-ribose) polymerase inhibitor Olaparib [42,46]. In the present case, the patient underwent optimal cytoreductive surgery with no macroscopically residual disease and started first-line platinum-based adjuvant chemotherapy paclitaxel/carboplatin/ bevacizumab. The treatment of OCS is summarized in Figure8[27–46]. Diagnostics 2020, 10, x FOR PEER REVIEW 11 of 15 Diagnostics 2020, 10, 1073 11 of 15

Fig.8 Ovarian carcinosarcoma treatment suggestion.

Figure 8. Ovarian carcinosarcoma treatment suggestion. In the present case, optimal cytoreduction was performed. Metastatic para-aortic lymph nodes wereIn the the only present extrapelvic case, optimal tumour cytoreduction dissemination. was Ligation performed. of the Metastatic inferior mesenteric para-aortic artery lymph (IMA) nodes werecould the be onlyapplied extrapelvic without any tumour clinical dissemination. consequences. Ligation Surgeons of ligate the inferior IMA either mesenteric directly arteryat the origin (IMA) couldof the be IMA applied from without the aorta any (high clinical ligation), consequences. or at a po Surgeonsint just below ligate the IMA origin either of directlythe left atcolic the artery origin of(low the ligation) IMA from [47]. the There aorta (highare two ligation), arterial orarches at a pointbetween just the below middle the origincolic artery of the (branch left colic of artery the (lowsuperior ligation) mesenteric [47]. There artery) are twoand arterialthe left archescolic artery between (branch the middle of the inferior colic artery mesenteric (branch artery), of the superior which mesentericmaximally artery) keep the and blood the left supply colic arteryto the (branchdescending of the colon inferior after mesenteric high ligation artery), of the which IMA. maximally The two keeparches the are blood marginal supply arterial to the arch descending (also known colon as after the artery high ligationof Drummond), of the IMA. and TheRiolan’s two archesarch [48]. are marginalAlthough arterial some reports arch (also showed known that as descending the artery ofcolo Drummond),n, ischemia or and necrosis Riolan’s might arch occur [48]. after Although high someligation reports of the showed IMA (especially that descending for patients colon, with ischemia advanced or rectal necrosis or sigmoid might occur cancer, after cerebrovascular high ligation ofdisease, the IMA and (especially hypertension), for patients in patients with without advanced gene rectalral disease or sigmoid they are cancer, less likely cerebrovascular to occur [48]. disease, and hypertension),Small bowel obstruction/ileus in patients without is a generalcommon disease reason they for readmission are less likely after to occur optimal [48 ].cytoreductive surgerySmall for bowel epithelial obstruction ovarian/ileus cancer, is a commonespecially reason after forpara-aortic readmission lymphadenectomy after optimal cytoreductive[49,50]. The surgerytreatment for of such epithelial an obstruction ovarian is cancer, decompression especially of the after bowel para-aortic by a nasogastric lymphadenectomy tube and aggressive [49,50 ]. fluid resuscitation. If conservative treatment fails for 72 h, the patient undergoes a relaparotomy [49]. The treatment of such an obstruction is decompression of the bowel by a nasogastric tube and In the present case, the reason for postoperative ileus was adhesion between the terminal ileum and aggressive fluid resuscitation. If conservative treatment fails for 72 h, the patient undergoes a the abdominal aorta. To the best of our knowledge, such a complication is reported for the first time relaparotomy [49]. In the present case, the reason for postoperative ileus was adhesion between the here, and it should be considered as a possible complication after para-aortic lymph node resection. terminal ileum and the abdominal aorta. To the best of our knowledge, such a complication is reported There are many studies suggesting prevention of postoperative ileus [51–55]. Intravenous for the first time here, and it should be considered as a possible complication after para-aortic lymph infusion of lidocaine decreases the risk of postoperative ileus by reducing pain and, therefore, node resection. sympathetic stimulation [51]. Preoperative probiotics administrations, COX-2 inhibitors and There are many studies suggesting prevention of postoperative ileus [51–55]. Intravenous infusion carbohydrate loading may have possible beneficial effect of postoperative ileus prevention [53]. A of lidocaine decreases the risk of postoperative ileus by reducing pain and, therefore, sympathetic study of 707 patients reported that immediate postoperative feeding and bowel stimulation with 30 stimulation [51]. Preoperative probiotics administrations, COX-2 inhibitors and carbohydrate loading mL of magnesium hydroxide (milk of magnesia) twice daily is a safe and effective approach to may have possible beneficial effect of postoperative ileus prevention [53]. A study of 707 patients preventing ileus in patients who undergo major gynecologic surgical procedures [54]. reported that immediate postoperative feeding and bowel stimulation with 30 mL of magnesium Currently, enhanced recovery after surgery (ERAS) protocols were adopted in gynecologic hydroxideoncology. (milkERAS of was magnesia) first used twice in daily colorectal is a safe surgery and eff ectiveand later approach in urology, to preventing vascular ileus surgery in patients and whogynecology. undergo ERAS major reduce gynecologic the rate surgical of postoperative procedures ileus [54]. by series general measures, such as early

Diagnostics 2020, 10, 1073 12 of 15

Currently,enhanced recovery after surgery (ERAS) protocols were adopted in gynecologic oncology. ERAS was ﬁrst used in colorectal surgery and later in urology, vascular surgery and gynecology. ERAS reduce the rate of postoperative ileus by series general measures, such as early feeding, avoidance of mechanical bowel preparation, opioid-sparing pain control, utilization of preoperative patient education, optimization of comorbid conditions, euvolemia, normothermia [51,52,55]. The strengths of the present case include: a brief review of OCS pathogenesis, prognosis, histology, and treatment summarized and illustrated in tables and ﬁgures. Retroperitoneal para-aortic lymph node metastasis is the only extrapelvic dissemination of OCS. The postoperative complication described has never been reported in the medical literature. The limitations of this case report include the following: levels of Ca125, preoperative computed tomography, clonality studies, patterns, genomic analysis, gene mutations and expressions were not performed.

4. Conclusions OCS is a rare disease with a dismal prognosis. Retroperitoneal, pelvic, and para-aortic lymph nodes should be closely inspected in patients with ovarian tumours. Retroperitoneal para-aortic lymph node metastasis could be the only extrapelvic dissemination of OCS. There are limited data on aetiology, diagnosis, prognostic factors and treatment of OCS. However, studies concluded that prognostic factors and treatment of carcinosarcomas are associated with epithelial components, as carcinosarcomas are carcinomas with epithelial–mesenchymal transition and heterologous diﬀerentiation [1,4,6,20–24,28–46]. Adhesion between the small bowel and the abdominal aorta leading to obstructive ileus is a possible complication after para-aortic lymph node dissection.

Author Contributions: Conceptualization S.K., and Y.K.; Methodology S.K., A.Y., and Y.I.; Formal Analysis S.S. (Stanislav Stoilov), Y.I., and S.K.; Investigation S.K., and D.D.; Resources D.J., Y.I., and S.K.; Data Curation S.S (Stanislav Stoilov); Writing—Original & Draft Preparation S.K.; Writing—Review & Editing S.S (Stanislav Slavchev), G.S., and Y.I.; Visualization D.D, and E.T.; Supervision A.Y. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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